Novel Therapies

The burgeoning understanding of the pathophysiology of AML has spurred the development of a host of investigational therapies. Table 4.1 lists a categorization of these therapies and classifies them into therapies that inhibit proliferation, promote apoptosis, improve chemotherapeutic effect, or work by immunotherapeutic means. Because AML is a rare disease that is already associated with fairly effective therapy, the challenge of bringing any of these therapies to improve the natural history of patients with AML is daunting indeed. Nonetheless, there have been two agents relatively recently approved for use in AML.

Table 4.1 Categories of novel therapies for AML

Drug-resistance modifiers Cyclosporine A Quinine PSC-833

Proteosome inhibitors (e.g., bortezomib)

Proapoptotic approaches (e.g., oblimersen and 18-mer anti-bc1-2)

Signal transduction inhibitors "RAS"—targeted (e.g., farnesyl transferase inhibitors, such as tipifarnib and lonafarnib) Tyrosine kinase targeted

FLT3 (e.g., PKC 412, CEP 701, and MLN 518) c-kit (e.g., imatinib)

Downstream signal inhibitors

Novel cytotoxic chemotherapy Nucleoside analogs (e.g., troxacitabine and clofarabine) Alkylating agents (e.g., amonafide)

Immunotherapeutic approaches Antigens known anti-CD33 (e.g. gemtuzumab ozogamicin) anti-GM-CSF receptor Antigens unknown stimulate immune system (IL-2 and GM-CSF) present tumor antigens effectively dendritic cell fusion transfer hematopoietic growth factor genes

Just as ATRA was first shown to be effective by investigators in the People's Republic of China,57 the first reports of the efficacy of arsenic trioxide58 also emanated from that country. Studies done at Memorial Sloan Kettering Cancer Center59 and at other US centers51 demonstrated that intravenously administered arsenic trioxide led to remission in 85% of patients with a relapsed APL. The biological effect of arsenic tri-oxide occurs via both a promotion of differentiation and an enhancement of apoptosis, but the precise biochemical mechanism remains elusive. The optimal setting for the use of arsenic trioxide in the initial management of AML is being studied as both an alternative to chemotherapy, when used with ATRA,60 and an early postremission consolidation. Toxicities of arsenic trioxide include prolongation of the QT interval, mandating the close monitoring of electrolytes and electrocardiograms.61

Approximately 90% of patients with AML have blasts that express the CD33 antigen on the cell surface8; consequently, the humanized monoclonal antibody toxin conjugate gemtuzumab ozogamicin binds to AML cells in 90% of cases. After binding to the cell surface and subsequent internalization, the acidic microenvironment results in release of the calicheam-icin toxin, which binds to double-stranded DNA, thereby promoting cell death. A phase I trial demonstrated the feasibility of the intravenous administration of gemtuzumab ozogamicin and was associated with some remissions in relapsed patients.62 The subsequent phase II trial involving 142 patients yielded a complete remission rate of 30% (half of whom had relatively low platelet count at the time of remis-sion).63 The phase II trial resulted in the approval of this agent for the treatment of older adults with relapsed AML not deemed to be chemotherapy candidates. As a single agent, significant activity seems to be limited to those with relapsed disease after an initial disease-free interval of at least 3-6 months. The role of gemtuzumab ozogamicin as an adjunct to chemotherapy or in minimal disease settings is being explored.

One of the most important strategies is harnessing our understanding of leukemic pathophysiology to design drugs which will inhibit signaling pathways promoting neoplastic cell growth and survival. Mutations in the FLT3 transmembrane tyrosine kinase occur in 30% of patients with AML. Such mutations are either a 3-33 amino acid repeat in the juxtamem-brane region (internal tandem duplication; ITD) which occurs in about 25%, or a point mutation in the so-called activation loop which resides in the cytoplas-mic tail (which has a 5% incidence).64 ITD mutations, particularly if they occur in a homozygous fashion,65 are associated with an adverse prognosis and may account for a subgroup of patients with normal kary-otype, who fare relatively poorly.66 FLT3 mutations have been preclinically shown to confer growth factor independence in leukemic cell lines and to produce a fatal myeloproliferative syndrome in murine models.64 Small molecules that inhibit FLT3 have been shown to kill such activated cell lines and model leukemias in mice. Early clinical trials with several FLT3 inhibitors have shown biological activity.6768 Farnesyl transferase inhibitors, such as tipi-farnib (originally thought to target a posttransla-tional modification of the ras proto-oncogene), also produce remissions in advanced69 and untreated older patients70 with AML.

There are several new chemotherapeutic agents, most notably the developmental novel nucleoside analogs troxacitabine71 and clofarabine,72 which have produced remissions in patients with relapsed and/or refractory AML. Certain agents such as oblimersen,73 an 18-mer nucleotide that inhibits the translation of the anti-apoptotic bc1-2 protein, are being developed, not as a single agent, but to enhance chemotherapeutic efficacy. One of the reasons for intrinsic disease resistance in certain AML patients, particularly those who are above 60, is the relatively high expression of proteins, such as MDR1, which confer drug resistance.74 Several clinical trials have attempted to determine whether so-called drug-resistance reversal agents can enhance chemotherapeutic efficacy. Although one randomized trial in relapsed AML showed a survival benefit when cyclosporine A was added to a salvage regimen containing ara-C and daunorubicin,75 other studies76 have been less promising.

Immunotherapeutic approaches remain a mainstay of therapy in AML, through the mechanism of graft versus leukemia noted following allogeneic stem cell transplantation.77 Allogeneic stem cell transplantation, discussed elsewhere, offers, albeit at a significant risk of treatment-related toxicity, an effective antileukemic approach. Whether such a "graft-versus-leukemia" effect can be harnessed without needing to employ high-dose chemotherapy or chemoradiation therapy and receipt of allogeneic stem cells is a subject of active research. Leukemia vaccines have been created, in some cases using leukemia-specific peptides which, presented in the context of an HLA molecule, could engender an immune response.78 Alternatively, manipulating tumor cells to allow more effective antigen presentation by either dendritic cell fusion79 or transfec-tion with a gene encoding a relevant cytokine80 may augment antitumor immunity. Generalized stimulation of the immune system with BCG was ineffective81; however, two major randomized trials conducted by the CALGB are determining whether interleukin-2,82 employed at the conclusion of all-planned postremission therapy, might decrease the relapse rate.

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